As demonstrated by U.S. Pat. No. 4,239,901 (Rainer) and Carney et al., "A Potent Non-Steroidal Anti-Inflammatory Agent: 2-[3-Chloro-4-(3-pyrrolinyl)phenyl]propionic Acid," Experientia, Vol. 29, page 938 (1973), it is known that chloronitrobenzene acetic acids and derivatives thereof are particularly useful intermediates for the synthesis of pharmaceuticals. Carney et al. show the utility of ethyl 2-(3-chloro-4-nitrobenzene)propionate in this regard, and Rainer teaches that polychloronitrobenzeneacetic acid esters are among the intermediates that can be used to prepare his pyrazol-1-ylphenylacetic acid and pyrazolinl-ylphenylacetic acid anti-inflammatory agents.
In the past, a disadvantage of employing chloronitrobenzeneacetic acids or esters, or the corresponding chloroaminobenzeneacetic acids or esters, as pharmaceutical intermediates has been the difficulty of preparing those intermediates by conventional techniques. Even the preferred procedures for preparing such compounds have proven to be tedious, difficult, and time-consuming operations. For example, as indicated in the Carney et al. article and in Example 23 of U.S. Pat. No. 3,868,391 (Carney et al. II), the conventional method of synthesizing esters of chloronitrobenzene or chloroaminobenzene alpha-methylacetic acids involves (1) alkylating a suitable polychloronitrobenzene with the diethyl ester of methylmalonic acid in the presence of a strong base, such as sodium hydride, and a suitable solvent, such as N,N-dimethylformamide or hexamethylphosphoramide, to form an ester of chloronitrophenyl-2-methylmalonic acid, (2) reducing the nitro group to an amino group when an amino compound is desired, and (3) subjecting the ester of the chloronitrophenyl or chloroaminophenyl-2-methylmalonic acid to hydrolysis, decarboxylation, and re-esterification--a reaction sequence that involved almost two days of refluxing in Example 23 of Carney et al. II. In a similar procedure found in his Example 16, Rainer's hydrolysis/decarboxylation step was conducted under reflux for five days.
Obviously, it would be a welcome contribution to the art to provide a method of synthesizing materials such as the aforementioned pharmaceuticals in a simple and straightforward manner without a need for the tedious and time-consuming operations associated with the conventional process approach.